Background: Antiangiogenic therapy has been a milestone in the treatment of metastatic renal cell carcinoma (mRCC) for years. The positive results with immune-checkpoint inhibitors (ICI) are changing the frontline standard of care of mRCC patients (pts). To date, prospective data are lacking to determine the efficacy of antiangiogenic therapy in pts progressed to ICI. The multikinase inhibitor Cabozantinib (cabo) has shown prolonged survival in pre-treated mRCC pts. Moreover, by targeting multiple pathways and crucial kinases involved in microenvironment-driven immune-escape, it may represent an ideal agent to be used sequentially after ICI. Methods: This is the first prospective open label, single arm, multicenter, phase II study to evaluate efficacy and safety of Cabo in pts with mRCC pre-treated with adjuvant or first line PD-1/PD-L1-based therapy (as monotherapy or in combination with an TKI or anti CTLA-4). Cabo 60 mg once daily was administered until progressive disease (PD) or unacceptable toxicity. The primary endpoint was progression free survival (PFS), secondary endpoints were overall survival (OS), objective response rate (ORR) and safety. Results: Among 23 patients enrolled, 22 were included in the analysis (one was excluded for screening failure). Median age was 59.5 years (range: 29-74), 69.5% were male. At baseline, Karnofsky performance status was 100 in 59% of pts, 80-90 in 31.8% and 70-80 in 9%. 22.7% of pts had a good Heng score, 50% intermediate and 27.2% poor. Median duration of the previous therapy with anti PD-1 or anti-PD-L1 compounds was 4.3 months. Pts received an average of 4.7 months of Cabo. Among evaluable cases, 6 pts (27.2%) achieved a partial response and 5 pts (22.7%) stable disease. The median follow-up was 7.2 months and the median PFS was 7.2 months. 2 pts discontinued treatment for toxicity, 8 pts for PD, 1 patient discontinued treatment for different reason than PD, 11 pts are still on treatment. Grade (G) 3 adverse events (AEs) occurred in 22.7% of pts; the most common AEs were hand and foot syndrome (HFS) (G1 in 36.3% of pts, G2 18.1%, G3 4.5%), diarrhea (G1 31.8%, G2 18.1%), hypothyroidism (G1 9.09 %, G2 22.7 %), mucositis (G1 36.3%, G2 4,5%), and fatigue (G1 18.1%, G2 18.1%). Transitory withholding of cabo was observed in 63.6% of pts (14/22) and it was due to AEs in the 90% of the cases. For 5/22 pts (22.7 %), dose reduction was needed to manage AEs. The most common AEs leading to temporary drug interruption were HFS G1-3 (13.9%), liver disfunction G1-G2 (13.9%), diarrhea G1-G2 (11.6%), nausea and vomiting G2 (11.6 %) and fatigue G2 (9.3%). Conclusions: So far, the treatment with cabo after a I line anti-PD-1 based immunotherapy resulted active and well tolerated. Clinical trial information: NCT03463681.